Advertisement

Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment; the PETIT study on severe hemolytic disease of the fetus and newborn

      Background

      Intrauterine transfusion for severe alloimmunization in pregnancy performed <20 weeks’ gestation is associated with a higher fetal death rate. Intravenous immunoglobulins may prevent hemolysis and could therefore be a noninvasive alternative for early transfusions.

      Objective

      We evaluated whether maternal treatment with intravenous immunoglobulins defers the development of severe fetal anemia and its consequences in a retrospective cohort to which 12 fetal therapy centers contributed.

      Study Design

      We included consecutive pregnancies of alloimmunized women with a history of severe hemolytic disease and by propensity analysis compared index pregnancies treated with intravenous immunoglobulins (n = 24) with pregnancies managed without intravenous immunoglobulins (n = 28).

      Results

      In index pregnancies with intravenous immunoglobulin treatment, fetal anemia developed on average 15 days later compared to previous pregnancies (8% less often <20 weeks’ gestation). In pregnancies without intravenous immunoglobulin treatment anemia developed 9 days earlier compared to previous pregnancies (10% more <20 weeks), an adjusted 4-day between-group difference in favor of the immunoglobulin group (95% confidence interval, –10 to +18; P = .564). In the subcohort in which immunoglobulin treatment was started <13 weeks, anemia developed 25 days later and 31% less <20 weeks’ gestation (54% compared to 23%) than in the previous pregnancy. Fetal hydrops occurred in 4% of immunoglobulin-treated pregnancies and in 24% of those without intravenous immunoglobulin treatment (odds ratio, 0.03; 95% confidence interval, 0–0.5; P = .011). Exchange transfusions were given to 9% of neonates born from pregnancies with and in 37% without immunoglobulin treatment (odds ratio, 0.1; 95% confidence interval, 0–0.5; P = .009).

      Conclusion

      Intravenous immunoglobulin treatment in mothers pregnant with a fetus at risk for hemolytic disease seems to have a potential clinically relevant, beneficial effect on the course and severity of the disease. Confirmation in a multicenter randomized trial is needed.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • de Haas M.
        • Thurik F.F.
        • Koelewijn J.M.
        • van der Schoot C.E.
        Hemolytic disease of the fetus and newborn.
        Vox Sang. 2015; 109: 99-113
        • Abbasi N.
        • Johnson J.A.
        • Ryan G.
        Fetal anemia.
        Ultrasound Obstet Gynecol. 2017; 50: 145-153
        • van Kamp I.L.
        • Klumper F.J.
        • Meerman R.H.
        • Oepkes D.
        • Scherjon S.A.
        • Kanhai H.H.
        Treatment of fetal anemia due to red-cell alloimmunization with intrauterine transfusions in The Netherlands, 1988-1999.
        Acta Obstet Gynecol Scand. 2004; 83: 731-737
        • Zwiers C.
        • Lindenburg I.T.M.
        • Klumper F.J.
        • de Haas M.
        • Oepkes D.
        • Van Kamp I.L.
        Complications of intrauterine intravascular blood transfusion: lessons learned after 1678 procedures.
        Ultrasound Obstet Gynecol. 2017; 50: 180-186
        • Yinon Y.
        • Visser J.
        • Kelly E.N.
        • et al.
        Early intrauterine transfusion in severe red blood cell alloimmunization.
        Ultrasound Obstet Gynecol. 2010; 36: 601-606
        • Canlorbe G.
        • Mace G.
        • Cortey A.
        • et al.
        Management of very early fetal anemia resulting from red-cell alloimmunization before 20 weeks of gestation.
        Obstet Gynecol. 2011; 118: 1323-1329
        • Poissonnier M.H.
        • Picone O.
        • Brossard Y.
        • Lepercq J.
        Intravenous fetal exchange transfusion before 22 weeks of gestation in early and severe red-cell fetomaternal alloimmunization.
        Fetal Diagn Ther. 2003; 18: 467-471
        • Howe D.T.
        • Michailidis G.D.
        Intraperitoneal transfusion in severe, early-onset Rh isoimmunization.
        Obstet Gynecol. 2007; 110: 880-884
        • Fox C.
        • Martin W.
        • Somerset D.A.
        • Thompson P.J.
        • Kilby M.D.
        Early intraperitoneal transfusion and adjuvant maternal immunoglobulin therapy in the treatment of severe red cell alloimmunization prior to fetal intravascular transfusion.
        Fetal Diagn Ther. 2008; 23: 159-163
        • Voto L.S.
        • Mathet E.R.
        • Zapaterio J.L.
        • Orti J.
        • Lede R.L.
        • Margulies M.
        High-dose gammaglobulin (IVIG) followed by intrauterine transfusions (IUTs): a new alternative for the treatment of severe fetal hemolytic disease.
        J Perinat Med. 1997; 25: 85-88
        • Connan K.
        • Kornman L.
        • Savoia H.
        • Palma-Dias R.
        • Rowlands S.
        IVIG–is it the answer? Maternal administration of immunoglobulin for severe fetal red blood cell alloimmunization during pregnancy: a case series.
        Aust N Z J Obstet Gynaecol. 2009; 49: 612-618
        • Gelfand E.W.
        Intravenous immune globulin in autoimmune and inflammatory diseases.
        N Engl J Med. 2012; 367: 2015-2025
        • van den Akker E.S.
        • Oepkes D.
        Fetal and neonatal alloimmune thrombocytopenia.
        Best Pract Res Clin Obstet Gynaecol. 2008; 22: 3-14
        • Margulies M.
        • Voto L.S.
        • Mathet E.
        • Margulies M.
        High-dose intravenous IgG for the treatment of severe rhesus alloimmunization.
        Vox Sang. 1991; 61: 181-189
        • Clark A.L.
        Clinical uses of intravenous immunoglobulin in pregnancy.
        Clin Obstet Gynecol. 1999; 42: 368-380
        • Thung S.F.
        • Grobman W.A.
        The cost effectiveness of empiric intravenous immunoglobulin for the antepartum treatment of fetal and neonatal alloimmune thrombocytopenia.
        Am J Obstet Gynecol. 2005; 193: 1094-1099
        • Kriplani A.
        • Malhotra Singh B.
        • Mandal K.
        Fetal intravenous immunoglobulin therapy in rhesus hemolytic disease.
        Gynecol Obstet Invest. 2007; 63: 176-180
        • Moise Jr., K.J.
        Management of rhesus alloimmunization in pregnancy.
        Obstet Gynecol. 2002; 100: 600-611
        • Mari G.
        • Deter R.L.
        • Carpenter R.L.
        • et al.
        Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses.
        N Engl J Med. 2000; 342: 9-14
        • Nicolaides K.H.
        • Soothill P.W.
        • Clewell W.H.
        • Rodeck C.H.
        • Mibashan R.S.
        • Campbell S.
        Fetal hemoglobin measurement in the assessment of red cell isoimmunization.
        Lancet. 1988; 1: 1073-1075
        • Austin P.C.
        An introduction to propensity score methods for reducing the effects of confounding in observational studies.
        Multivariate Behav Res. 2011; 46: 399-424
        • Lindenburg I.T.
        • Smits-Wintjens V.E.
        • van Klink J.M.
        • et al.
        Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study.
        Am J Obstet Gynecol. 2012; 206: 141.e1-141.e8
        • Santos M.C.
        • Sa C.
        • Gomes Jr., S.C.
        • Camacho L.A.
        • Moreira M.E.
        The efficacy of the use of intravenous human immunoglobulin in Brazilian newborns with rhesus hemolytic disease: a randomized double-blind trial.
        Transfusion. 2013; 53: 777-782
        • Smits-Wintjens V.E.
        • Walther F.J.
        • Rath M.E.
        • et al.
        Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial.
        Pediatrics. 2011; 127: 680-686
        • Steiner L.A.
        • Bizzarro M.J.
        • Ehrenkranz R.A.
        • Gallagher P.G.
        A decline in the frequency of neonatal exchange transfusions and its effect on exchange-related morbidity and mortality.
        Pediatrics. 2007; 120: 27-32
        • Orchard C.
        Comparing healthcare outcomes.
        BMJ. 1994; 308: 1493-1496
        • Austin P.C.
        • Stuart E.A.
        Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies.
        Stat Med. 2015; 34: 3661-3679

      Linked Article

      • Revisiting the use of intravenous immune globulin (IVIG) for Kell alloimmunization
        American Journal of Obstetrics & GynecologyVol. 219Issue 3
        • Preview
          The development of anti-D (Rh) immune globulin and its antepartum and postpartum use is one of the remarkable success stories in obstetrics as it has nearly eliminated fetal deaths from Rh immunization. In contrast, Kell immunization, although rare, is still present since there is no prophylactic anti-Kell immune globulin. The critical titer for identifying affected pregnancies and optimal care of Kell-sensitized pregnancies has remained controversial.1,2 When severe Kell alloimmunization occurs, intrauterine blood transfusion is essential to prevent fetal death.
        • Full-Text
        • PDF